Effects of long-term dipeptidyl peptidase-IV inhibition on body composition and glucose tolerance in high fat diet-fed mice

AimGlucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are major incretins associated with body weight regulation. Dipeptidyl peptidase-IV (DPP-IV) inhibitor increases plasma active GLP-1 and GIP. However, the magnitude of the effects of enhanced GLP-1 and GIP signaling by long-term DPP-IV inhibition on body weight and insulin secretion has not been determined. In this study, we compared the effects of long-term DPP-IV inhibition on body composition and insulin secretion of high fat diet (HFD)-fed wild-type (WT) and GLP-1R knockout (GLP-1R−/−) mice.Main methodsHFD-fed WT and GLP-1R−/− mice were treated with or without DPP-IV inhibitor by drinking water. Food and water intake and body weight were measured during 8 weeks of study. CT-based body composition analysis, Oral glucose tolerance test (OGTT), batch incubation study for insulin secretion and quantitative RT-PCR for expression of incretin receptors in isolated islets were performed at the end of study.Key findingsDPP-IV inhibitor had no effect on food and water intake and body weight, but increased body fat mass in GLP-1R−/− mice. DPP-IV inhibitor-treated WT and GLP-1R−/− mice both showed increased insulin secretion in OGTT. In isolated islets of DPP-IV inhibitor-treated WT and GLP-1R−/− mice, glucose-induced insulin secretion was increased and insulin secretion in response to GLP-1 or GIP was preserved, without downregulation of incretin receptor expression.SignificanceLong-term DPP-IV inhibition may maintain body composition through counteracting effects of GLP-1 and GIP while improving glucose tolerance by increasing glucose-induced insulin secretion through the synergistic effects of GLP-1 and GIP.